Bioequivalence 2

Question 1

What are BE studies required for?

Answer 1

any new generic product
an innovator manufacturer to show product to be marketed is BE with the formulation used in clinical trials
innovator manufacturer changes formulation of drug on the market or introduces additional dosage strengths
considering new route of administration

Question 2

What are some cases where a waiver of BE would be allowed?

Answer 2

some drugs, in vivo BA may be self-evident or not important to products intended purpose
-solution intended for IV use
-topical applied for local use
-oral dosage form not intended to be absorbed
-administered by inhalation
-solution, elixir, syrup, tincture, etc. form of an approved product and contains no inactive ingredients known to affect BA
class I BCS drugs

Question 3

By descending order of preference, which types of bioequivalence studies are preferred by US-FDA and CAN-TPD?

Answer 3

pharmacokinetic study (PK-BE)
pharmacodynamic study (PD-BE)
comparative clinical study
in vitro study (dissolution study, BCS biowaivers)

Question 4

When are PD-BE studies used?

Answer 4

when PK approach not possible
-i.e., locally acting drug product

Question 5

What do PD-BE studies assess?

Answer 5

uses a pharmacological or clinical endpoint
-e.g., FEV for inhaled bronchodilators

Question 6

What are PD parameters?

Answer 6

AUC of the PD effect vs time curve
peak PD effect
time for peak PD effect

Question 7

Why are many PD tests difficult to quantify?

Answer 7

placebo effects (increase sample size)
PD variability is large (increase sample size)

Question 8

What is required for PD-BE studies?

Answer 8

must be validated (accurate, sensitive, reproducible)
demonstration of a dose-response curve
doses should produce a range of response values
instrumental measurements should be made under double-blind conditions

Question 9

When are clinical studies used for BE?

Answer 9

when neither PK nor PD approach possible

Question 10

How is BE established in clinical studies?

Answer 10

uses a controlled clinical blind or double blind study –> BE established through evaluation of clinical response

Question 11

What is used to establish BE for topical antifungal drug products?

Answer 11

clinical studies

Question 12

What are the disadvantages of clinical studies for BE?

Answer 12

least accurate, least sensitive, least reproductive
considered only when analytical and PD not available

Question 13

What are PK-BE studies?

Answer 13

uses PK measures to determine rate/extent of drug release from product and absorption into systemic circulation

Question 14

What is used in PK-BE studies to reflect important differences in T vs R?

Answer 14

exposure concept of BE
-total exposure (AUC for single dose, AUC for multiple dose)
-peak exposure (Cmax)
-early exposure (partial AUC to peak time)

Question 15

What would the ideal subject be for BE studies?

Answer 15

normal, healthy volunteers
-age 18-55, BMI 18.5-30, normal med exam, no alcohol or drug use, ECG if drug impacts, not pregnant/lactating
may be necessary to conduct studies in pts who are already receiving the drug

Question 16

What should be considered in the study design of BE studies?

Answer 16

the three fundamental statistical concepts of study designs:
-randomization (allot tx to subjects without selection bias)
-replication (tx applied to more than one experimental unit)
-error control (reduce sources of experimental error)

Question 17

What is involved in a typical single oral dose (SOD) design?

Answer 17

2 product
2 period
2 sequence
crossover

Question 18

Differentiate crossover and parallel study design.

Answer 18

crossover:
-diminished intrasubject variation and allows examination of intrasubject variation
-replicated cross-over designs: formulations tested more than once in the same subjects
-more periods and sequences: more than two formulations, or different study conditions
parallel:
-does not allow within-subject comparison (need to increase n)

Question 19

When do we consider using parallel study design for BE?

Answer 19

drug has very long t1/2
some depot formulations

Question 20

What does the number of subjects with desired power and significance level depend on?

Answer 20

mean difference between T and R (+/- 20%)
intra-subject variance
power (typically 0.8)
type I error rate of 5%

Question 21

What is the minimum number of subjects needed for BE studies?

Answer 21

12
-or determine intra-subject variance from first stage then expand the study
-accounting for drop-outs
-accounting for outliers

Question 22

What are the standardized study conditions for BE studies?

Answer 22

posture, exercise, diet, smoking, alcohol, other drugs
dietary items that effect P450 enzymes and PGP efflux pump
blinding
-subjects, person checking for AE, analyzer
control food and fluid administration
-fast 8h, water consumed up to 1h before admin
-dose at same time every day
-dose taken with 150-250ml of water
-water and food 1 and 4h after

Question 23

Describe proper conduct of a BE study.

Answer 23

subject takes T or R with 150-250ml water
blood samples taken at intervals to define Cp vs t curve
-minimum 12 samples per subject per dose
-sample for at least 3 half lives
plasma collected and frozen
allow sufficient washout (>10h t1/2) then next formulation taken
monitor and record AE
validated assay determines drug concentration

Question 24

Which design is used for most BE studies?

Answer 24

SOD

Question 25

What are advantages of multiple-dose administration for BE studies?

Answer 25

for pts who it would be unethical to d/c tx
do not need to extrapolate to get total AUC
more closely reflects clinical use of drug
allows Cp measured at therapeutic levels
can detect nonlinear PK

Question 26

What are disadvantages of multiple-dose administration for BE studies?

Answer 26

more time and more difficult and costly
issues with compliance control
increase potential for AE

Question 27

What are the parameters used to characterize rate and extent of bioavailability for single dose?

Answer 27

AUC
Cmax
Tmax

Question 28

What are the parameters used to characterized rate and extent of bioavailability for multiple dose?

Answer 28

AUC
% fluctuation

Question 29

What is involved in the statistical assessment of PK-BE studies?

Answer 29

Cp vs time curve constructed
-summary of drug [] at each time point for each subject
calculate important PK parameters for T and R
-AUC, Cmax, Tmax

Question 30

What needs to be examined to confirmed/refute BE?

Answer 30

examine PK criteria according to set of predetermined criteria
mean AUC or Cmax of T had to be within +/- 20% of R

Question 31

Why do we do logarithmic transformation of BE metrics?

Answer 31

PK parameters of Cp vs t are log normally distributed
-for AUC and Cmax, distribution is skewed and variances increase with the mean value
-log trans makes variances independent of the means and symmetrical distribution
primary comparison of interest in BE study is the ratio rather than the differences between average parameter data
-log trans achieves this
examine difference in means of Cmax and AUC between T and R
-Cmax and AUC must be log trans before statistical analysis

Question 32

What is the confidence interval approach?

Answer 32

two one-sided tests: if the F of T formulation is too high or low
-90% CI for the ratio of means 0.8-1.2
-when log trans data is used, the 90% CI is 80-125%

Question 33

What are the predominant issues with BE studies?

Answer 33

PK criteria
-BE measures expressed in systemic exposure measures
-assume these measures relate to safety and efficacy outcomes
statistical criteria

Question 34

What are the approaches for BE comparisons?

Answer 34

average BE
-typical BE comparison
-focuses on comparison of population averages of BE
population BE
-relies on population estimates
-determines total variability of the BE in population
individual BE
-considers the individual
-assesses within-subject variability of T and R products and subject-by-formulation interaction
population and individual BE
-compares both means and variances of a BE measure

Question 35

What does the statistical model assume?

Answer 35

normality
-log normal distribution of random variables
independent
-random variables are independent
homoscedasticity
-variance of dependent variable is constant and does not change with independent variable

Question 36

What does comparisons for BE rely on?

Answer 36

a criterion (to base comparisons)
a CI for the criterion (provides the statistics to determine difference)
a predetermined BE limit (determine whether the relative BA is acceptable)